In pyrimidine chemistry, for the majority of nucleophilic substitution reactions involving 2,4-functionalized pyrimidines and amines it is known that the first amine addition occurs preferentially (or exclusively) at the more reactive pyrimidine 4-position.
The reaction of pyrimidines of formula I′ (where X is a leaving group; most commonly a halogen, particularly chlorine) and amines of formula II usually provides mixtures of regioisomers of formulae III′ (2-amino pyrimidine derivatives) and IV′ (4-amino pyrimidine derivatives) (see Scheme 1 below). Examples for such unselective reactions can be found in the art, inter alia, for the electron deficient 2,4-dichloro-5-trifluoromethylpyrimidine.

Thus, usually, the reactions of 2,4-dichloropyrimidine derivatives with amines provide non-selective mixtures of 2-chloro-4-amino-pyrimidines and isomeric 2-amino-4-chloropyrimidines in such that these reactions are of limited utility not only due to their lack of selectivity (and its impact on overall yield) but also because separation of the resulting isomers is generally extremely difficult and may require preparative HPLC, which is often not desired in a process sequence.
In contrast, there are only few examples where an amine is added to a 2,4-dichloropyrimidine in a selective manner to provide preferentially the 2-amino-4-chloropyrimidine. The most notable example of this type of reaction can be found in the international application WO 2005/023780 which describes a method for selective addition of an amine functionality to the C-2 position of a CF3-substituted pyrimidine ring in the presence of a Lewis Acid (namely a salt of a metal ion) and a non-nucleophilic base.
However, there remains a need in the art for providing methods for obtaining efficiently compounds of formula III′. Further, there remains a need in the art for selective addition of amines to the usually less reactive C-2 position of pyrimidines which are substituted at C-5 position by CF3. Further on, there remains a need in the art for efficient providing compounds of formula III′ vis-à-vis unselective regioisomeric mixtures.
Other aims of the present invention will become apparent to the skilled man from the foregoing and following remarks.